Tubercle, Lond., (x959), 4o, 413

O R I G I N A L ARTICLES

An Estimation of the Scope for BCG Vaccination in Preventing Tuberculosis among those aged i 5 - i 9

Years in England and Wales at the Present Time By IAN S U T H E R L A N D

from the Statistical Research Unit of the Medical Research Council, London School of Hygiene and Tropical Medicine, Keppel St, London

All estimate of tile benefit to be expected from BCG vaccination of those tuberculin- negative at tile age of 14 years was made recently in tlle second report of the Medical Research Council's Tuberculosis Vaccines Clinical Trials Committee (Medical Research Council, x959). Tile M.R.C. trial, however, began in 195o , and since then there have been substantial decreases in England and Wales, both in the proportions of children who have been infected by a given age (that is, who are tuberculin-positive), and in the risk of exposure to tuberculous infection in adolescence. The main purpose of this essay is, by taking these changes into account, to estimate what reduction in the incidence of tuberculosis, and in the numbers of cases, among those aged i5 - i 9 years in England and Wales at the present time, could have been achieved had BCG vaccine been given at the age of 14 years to all who were then tuberculin-negative. At the end of 1953 a national scheme was

b e g u n for the B e G vaccination of those tuberculin-negative at the age of 13 years, and this paper also provides estimates of its effect so far.

The M.R.C. estimate of the benefit of BCG vaccination at the age of 14 years was based upon a population of about 56,7oo, which included both those tuberculin-positive as well as those tuberculin-negative at that age. The percentage reduction in the incidence of tuberculosis during a five-year period, if all those tuberculin-negative on entry (at the age of 14 years) had been vaccinated with BCG, would have been 59 per cent. This assessment related to a particular section of the urban population of Britain, for which observation began in 195o-52 and extended for a five-year period. For those reaching the age of 14 years since x952 , however, ' there has been a decrease in the exposure to tuberculous infection in the young adult age group, which, by decreasing the cases to be expected in the tuberculin-negative group, and leaving those in the positive groups largely unaffected, would tend to decrease the benefit. But there has also been a notable decline in the prevalence of tuberculin sensitivity to 3 T U in those aged I3 - I 5 years (compare M.R.C., 1958, with M.R.C., i956), which, by increasing the proportion of the population group eligible for vaccination, would tend to increase the benefit' (Medical Research Council, 1959). To obtain a fair estimate of the scope for BCG vaccination in preventing tuberculosis at the present time, it is thus necessary to assess the influence of these trends. I t is also necessary to generalize from the M.R.CI. trial population to that of England and Wales.

The most recent year for which relevant information is fully available is 1958. The benefit to those aged x5-19 years in England and Wales in 1958, as a result of BCG vaccination at the age of 14 years of all who were then tuberculin-negative, will be estimated from these data.

414 TUBERCLE

THE ESTIMATION PROCESS

Cases of Tuberculosis Adjusted Notifications

O O o

r e~

C~

--d c0

<

2.0

1.0

In t h e M.R.C. t r ia l

I I

i

/

In a similar

population aged

15-19 years in 1958

?

I Rates attributable t o those

In England and Wales among those

aged 15-19 years in 1958

Without BCG vaccination

/>

With BCG vaccination

2> Preventable

by BCG

Occurring despite BCG

----] tubercul

I tubercul

in-negative

in-positive a t 14 y e a r s

F,o. I. - The estimation process (tile three stages of the process are indicated by the arrows).

M e t h o d T h e es t imat ion has three main stages, i l lustrated in Fig. I :

i . A popu la t ion with a socio-economie backg round s imilar to tha t of the M.R .C . tr ial is considered. T h e propor t ions of such a popu la t ion with var ious degrees of tubercul in sensi t ivi ty at the age of 14 years are es t imated for each of the ca l enda r years x953 to 1957 ( that is, for the five ' cohor ts ' o f I4-year -o ld chi ldren who became 15- i 9 years of age in 1958 ) . T h e inc idence o f tuberculosis in the year r958 a t t r i bu t ab l e to the taberculhz-positire sections o f each of these five cohorts is es t imated fi'om the findings for the t t ,bercul in-posi t ive groups in the follow-up of the M.R .C . t r ia l ; the five rates are averaged to give a single ra te for the 15- i 9 year age group in x 958.

2. This es t imate of the incidence of cases of tuberculosis a t t r i bu t ab l e to the tubercul in-posi t ive sections of a popu la t ion s imilar to tha t of the M.R.C. trial in I958 is then conver ted to an es t imate of the inc idence of notif ications o f tuberculosis a t t r i bu t ab l e to the same sections of the popu la t ion of the whole country, also in 1958. T h e re la t ionship between the incidence of tuberculosis discovered in the first five years of fol low-up in the M.R .C . trial and the not if icat ion ra te a t ages 15- , 9 years in Eng land and Wales over the same per iod provides an a p p r o p r i a t e conversion factor.

3. T h e above p rocedure yields an es t imate of that pa r t of the not if icat ion ra te

TIlE SCOPE. FOR BCG VACCINATION 4 x 5

at ages 15-i 9 years in England and Wales in 1958 , attributable to those who had been tubereulhz-positive at the age of 14 years. The difference between this figure and the total notification rate at ages i 5 - i 9 years thus represents that part of the rate attributable to those tuberculbz-negalive at the age of 14 years. The reduction in incidence of tuberculosis, by BCG vaccination of all tllose tuberculin-negative at the age of 14 years in England and Wales, may then be estimated from the degree of protection shown in the M.R.C. trial. Finally, the reqnircd estimate of the benefit to the entire population, tuberculin-positive and negative combined, may be derived.

The above approach, via the experience of those tuberculin-positive at the age of 14 years, may at first seem to be unnecessarily roundabout. There is, however, evidence that the subsequent incidence of tuberculosis in those known to be tuberculin-positive is much less influenced by the level of tuberculous infection in the community than the subsequent incidence in those known to be tuberculin- negative (Medical Research Council, I959, p. 39~ In a community in which the level of tuberculous infection is changing rapidly, as in England and Wales at the present time, a direct estimate of the latter incidence might therefore be very Inaccurate.

The successive stages of this approach will now be worked through in detail .in deriving the estimate, for I958 , of the benefit of BCG vaccination. The various assumptions involved will be described, and their importance indicated, in the course of the argument.

S tage x

hwidence of tuberculosis in I958 among those tuberculhz-positive at the age of I4 9"ears Section A of Table I contains estimates of the percentages of t4-year-old children

in each of the years 1953 to I957, in a population with a similar background to that of the M.R.C. trial, who had strong positive reactions to 3 T U (I 5 mm. induration or more), weak positive reactions to 3 T U (5-14 mm. induration) or were negative to 3 T U but had positive reactions to too "I"U (5 mm. induration or m o r e ) - t h e three degrees of positivity identified in the M.R.C. trial. These estimates were derived by interpolation between tile results of the initial tuberculin tests of those aged 14 years in all three areas of the M.R.C. trial, nearly all made in 195i and 1952 , and the resuhs of corresponding tests of closely similar populations

TABLE I . - ESTIMATED PERCENTAGES TUBERCULIN-POSITIVE AT TIIE AGE OF t 4 ~IrEARS FROM 1953 TO 1957, AND I']STIMATED INCIDENCE OF "I'unERCULOSlS IX I958 , ~X a POPULATION SIMILAR TO TIIAT OF

T H E M . R . C . TRIAL

1"ear when the

population 'cohort '

was aged z 4 years

1953 x95-~ 1955 x956 1957

Age of the

cohort in z956 (9'ears)

19 18 17 16

Section A Section B

Effimated incidence of Estimated pereentages of each tuberculosis b~ t958 per t ,ooo

cohort who had different persons who had different degrees of tuberculbt positirity degrees o f tuberculbt positirity

at the age of z4years at the age of t4years

3 T U

x 5 mm. indur- 5 - z 4 ram. ation indur-

or more allon

t z t 4 IO 1 2 8 1I 7 9 6 8

zoo T U Dil ly

5 nun. indur- ation

or tnore

z4 t5 t5 t6 16

3 T U

x 5 mm. indur- 5 - r4mm. ation indur-

or more a l ton

t "4 o .8 2 .o o .8 2.6 o .8 3"~ o.8 3"8 o.8

1oo T U Dilly

5 mm. indur- ation

or tnore

o- 9 o" 9 o- 9 o" 9 o ' q

Section C

That part of the incidence of

tuberculosis bt t958 per t ,ooo population,

attributable lo those tuberculbt-positi~'e

at the age of t4years

0"392 ] 0-431 | o-43 t ~ A v e r a g e : o - 4 4 o / o ' 4 ~ 6 o.436 J

416 TUBERCLE

of the same age in the same three areas in 1957 (see Medical Research Council, 1958, for the London area). These results have not yet been published in detail, but are believed to give a trustworthy indication of the levels of tuberculin positivity in this section of the population in I951-52 and 1957 respectively. Inaccuracies in the estimates derived from them are thus likely to be slight, and should not seriously affect the reliability of subsequent calculations. The estimates in Table I show that there have been substantial decreases during the period 1953 to 1957 in the percentages with strong and weak positive reactions to 3 T U , and a small increase in the percentage positive only to IOO T U .

Section B of Table I contains estimates of the incidence of tuberculosis in 1958 at each age from 15 to 19 years, among those who had each of the three degrees of tuberculin positivlty at the age of 14 years. These estimates were derived directly from detailed findings on tlle incidence of tuberculosis in the same three tuberculin- positive groups in the M.R.C. trial. The annual incidences tabulated for the group with strong positive reactions to 3 T U were obtained by fitting a regression line to the six-monthly totals of cases of tuberculosis starting in the first five years of follow-up in that trial. There was no obvious secular trend in incidence for the other two positive groups, and tile average was therefore used.

When these incidences are applied to the cohorts aged 14 years in I953 to 1957, as will be done in the next paragraph, it is assumed that these rates, appropriate to the M.R.C. trial cohorts of 1951-52 , are also appropriate to the later cohorts. In other words, it is assumed that in this section of the general population the development of tuberculosis in those already tuberculin-positive at the age of 14 years is independent of subsequent exposure to the disease. As already indicated above, some evidence of the validity of this assumption was discussed in the second rcport of the M.R.C. trial (Medical Research Council, I959, p. 392). I t represents one of the main assumptions on which this paper is based.

Section C of Table I shows the incidence of tuberculosis in 1958 attributable to those who had been tuberculin-positive at the age of 14 years. The incidence in each cohort is calculated by applying the rates in Section B to the appropriate percentages in Section A. For example, the expected incidence of tuberculosis in the cohort aged 19 years in 1958 , contributed by those tuberculin-posltive at the age of l 4 years, is calculated as: (1i • i . 4 + 14 X 0.8 + 14 X o"9)+IOO=O"392 per I,OOO. The corresponding estimates at ttle ages of 18, 17, 16 and 15 years are o'431, o-43 I, o.44o and o.436 per I,OOO respectively, giving an average of o.426 per I,ooo populatlon aged I5-19 years. I t should be emphasized that this figure represents only part of the expected incidence of tuberculosis in 1958 in those aged I 5 - I 9 years, namely that attributable to those already tuberculin-positlve at the a g e o f 14 years.

Stage 2 This estimate of tile incidence of tuberculosis in 1958 in a population with a similar background to that of tile M.R.C. trial must now be converted to an estimate appropriate to the population of England and Wales. To do this it is necessary to compare the incidence of tuberculosis in the M.R.C. trial with the notification rate for the whole country in the same age group over the same period.

I t was estimated in the second report of the M.R.C. trial (Medical Research Council, I959) that a total of 55 ~ cases of tuberculosis would have been expected within five years of entry in the entire population of 56,7oo (tuberculln-positive and negative combined) in the absence of vaccination. This represents an annual incidence of 1.94o per 1,ooo population. This figure must be compared with a national notification rate, also estimated in the absence of vaccination.

The official scheme for the BCG vaccination of 13-year-old children in Britain (Ministry of Health, i953) began at the end of i953. A small proportion of the population of England and Wales in the 15-i 9 year age group in 1956 , and larger

T I I E SCOPE FOR I~CG VACCINATION 417

TABLE I I . - Tim EXTENT OF TIlE OFFICIAL SCIIEME FOR BCG "VACCINATION OF 13-YEAR-OLD ClnLDREN IN ENGLAND AND ~rALES FROSt 1954 TO 1958

~ar

x954 1955 1956 1957 I958

'Home' population aged 13 )'ears

(a)

591,ooo * 61 i,ooo* 629,000 664,ooo 658,ooo

Tuberculin tested No. % (b) of (a)

219,636 34"9 ~ 44"5 3o6,74t 46"6

Tuberculin 'positive' ~'o. %

of (b)

48,827 ee.e 57,7513 x9"6 54,779 r7"9

Vaccinated with BCG ~Vo. %

of (~)

43,765 7"4 134,3o8 .~2.o 166,o79 ~6" 4 ~33,254 35"r ~41,-1-34 36"7

Sources: Home population: The Registrar-General's Statistical Review of England and Wales, Part I. Tables, Medical.

Numbers tuberculin tested, and tuberculin-posltive: Report of the Ministry of Health, Part I. Numbers vaccinated: Report of the Ministry of Health, Part II (for 1956 to x958 also in

Part I). *Estimated by taking one-fifth of the home population aged Io-I 4 years.

p r o p o r t i o n s in s u b s e q u e n t years , wi l l t h u s h a v e b e e n g i v e n B C G v a c c i n e u n d e r th i s s c h e m e , a n d wil l t h e r e b y h a v e r e c e i v e d s o m e p r o t e c t i o n a g a i n s t t u b e r c u l o s i s . A n a d j u s t m e n t is t h e r e f o r e n e c e s s a r y to t h e n o t i f i c a t i o n ra t e s for i 9 5 6 to 1958 to a l l o w for t h e ef fec t o f th i s s c h e m e .

T h e r e is a lso a n off icial s c h e m e , w h i c h b e g a n in I949 ( M i n i s t r y o f H e a l t h , I 949 ) , for t i le B C G v a c c i n a t i o n o f t u b e r c u l i n - n e g a t i v e c o n t a c t s o f k n o w n cases o f t u b e r c u l o s i s . H o w e v e r , n o a d j u s t m e n t s a r e n e e d e d for this , b e c a u s e i t cover s c o n t a c t s o f al l ages, so t h a t its i n f l u e n c e a t ages 1 5 - 1 9 yea r s is sma l l . National Notification Rates at Ages i 5 - I 9 Years h, the Absence of the Offeial Scheme for BCG Vaccination at the Age o f 13 Tears

The way in which the national notification rates were adjusted will be outlined for the ycar 1958. The first step is to determine what proportion of the population at ages t5- I9 years had been vaceinatcd under the official scheme. Table II summarizes the extent of tile scheme from its start, at the end of x953, until 1958. The total vaccinated in the three years I954-56 was 344,15~. The total number of 13-year-old children in these three )'ears was x,831,ooo. These children, together wi!h those aged t 3 years in t952 and 1953 (numbering 1,I42,ooo* ) became the 15-t 9 year age group In t958. The proportion of this entire age group which was vaccinated is thus 344,152-(I ,831,ooo+ t,142,ooo ) = t x-6 per cent.

The effect on the notification rate of BCG vaccination of I 1"6 per cent of those aged 15-I 9 years in 1958 can only be assessed precisely if, in addition, the proportions of the population who were tuberculin-positive and tuberculin-negative at the age of 13 years are known, as well as the relative magnitude of the notification rates at ages x5-19 years in these two sections of the population. This information is not available for the whole country, and cannot be estimated with great reliability from the findings in the M.R.C. trial. Fortunately, however, it happened that the notification rates in these two sections of the population were of similar magnitude in the year t958; if it is assumed, as a first approximation, that they were equal, the proportions of the population who were tuberculin- positive and tuberculin-negative at t 3 years are unnecessary for the calculation of the effect of BCG vaccination, and the calculation itself is thus simplified.

The effect of BCG vaccination was to reduce the notification rate in I i .6 per ccnt of the population by a proportion taken as 83.3 per cent, this being the level of protection in the first five years of follow-up in the M.R.C. trial (Medical Research Council, ,959). On the above assumption, this represents a reduction of 9"7 per cent in the rate in the whole population. The actual notification rate for 1958 (o'881 per t,ooo -see Table II1) thus represents 9o'3 pcr cent of the notification rate to be estimated. The adjusted notification rate for 1958 is therefore estimated as o-88x • Ioo+9o '3=o '976 per 1,ooo population aged 15-t 9 years.

In order to improve this estimate, a closer approximation was derived for the relative magnitude of the notification rates at ages x5-19 years in x958 in those tuberculin-positive and those tuberculin- negative at the age of 13 years. Without going into the details, the effect of using this more accurate estimate was to decrease the adjusted notification rate for 1958 by o.olo to 0-966 per i,ooo.

The notification rates for t956 and 1957 were adjusted similarly.

The Correspondence Between the Five-year hzcidence of Tuberculosis it, the ~ILR.C. Trial and the Notification Rate of Tuberculosis at Ages I 5 - 1 9 Years hi England and Wales

T a b l e I I I shows t h e p o p u l a t i o n o f E n g l a n d a n d W a l e s a g e d x5-x 9 yea r s f r o m x95 o *Estimated by taking one-fifth of the home population aged to-I 4 years in each year.

418 TUBERGLE

TABLE III. -- ~-'N'OTIFICATIONS OF ALL FORMS OF TUBERCULOSIS AT AGES 15--I 9 YEARS IN ENGLAND AND ~'ALES PROM 1950 TO 1958 , AND TIIE PROPORTIONS OF EACII CALENDAR YEAR INCLUDED IN TIIE

FIRST FIVE YEARS OF FOLLOXV-UP IN TIIE M . R . C . TRIAL

1"ear

195o 195I 1952 I953 1954 I955 1956 1957 1958

'Home' population of England and

IVales at ages 15-z 9.)'ears

2,736,000 2,715,OOO 2-~715,OOO 2,743,000 2,745,ooo 2,774#oo 2,755,000 2,785,ooo 2,134o,ooo

Notifications of tuberculosis (all forms) in England and lVales at ages 15-I9 years

Rate Adjusted ~Vo. per i,ooo rate*

5,853t 2"139 - - 5,67ot 2.o88 - - 5,325t x'96I - - 4,948 1"8o4 - - 4,647 1"693 - - 4,147 I'495 - - 3,475 1.261 1-279 2,956 I'O6I 1.1I 7 2,5oi o'88I o-966

l'roportions of each calendar year included in the first five

years of follow-up of participants in the 31.R.C. tria~

0-0035 o'3o54 o.7926 I'OOOO I'OOOO o'9965 o.6946 o'~o74

Sources: Home population: The Registrar-General's Statistical Review of England and Wales, Part I. Tables, Medical.

Notifications of tuberculosis, I95O-52 : Report of the .Ministry of Heahh, Part II. 1953-58: Ministry of Health (personal conununlcation).

*The rate expected in the absence of the official scheme for BCG vaccination at tlle age of 13 )'ears. 1-Estimated by taking 45 per cent of the published notifications at ages !5-24 ),ears, tiffs being the

proportion found both in 1953 and in 1954.

to 1958 , the numbers of notifications of all forms of tuberculosis in this age group, the corresponding notification rates per 1,ooo populat ion, and the adjusted rates in 1956, I95 7 and 1958 in the absence of the official scheme.

T o establish the required correspondence between the incidence in the M.R.C. tr ial and the notif ication rate in the whole country, the na t ional notif ication rates must be averaged suitably. Because the intake in the M.R.C. trial took more than two years, the five-year follow-up was not completed unt i l more t han seven years after the start. Therefore, to make the comparison relate to the same period of t ime as the five years of follow-up in the M.R.C. trial, a weighted average of the na t ional notification rates from 195o to 195 7 is needed, the weights represent ing the proportions of those years included in the follow-up. These weights were calculated from detailed intake figures for the M.R.C. trial, and are also shown in Ta b l e I I I .

Applying tbe weights to the notification rates (adjusted where necessary) the average a n n u a l notification rate corresponding to the first five years of follow-up in the M.R.C. trial is calculated as ( 2 . 1 3 9 • 2 1 5 . . . . . . + 1-117 • o'2o74) + 5 = 1.661 per I,OOO popula t ion at ages i 5 - I 9 years. Ttle incidence of tuberculosis in the trial popula t ion wi th in five years of ent ry in the absence of vaccinat ion (1.94 ~ per I,ooo) thus exceeds the corresponding na t iona l notif ication rate at ages x5-x 9 years by I6.8 per cent.

A m o n g the possible reasons for this difference are deficiencies in the notifications*; differences in exposure to infection between the trial populat ion, consisting of volun- teers, and the na t iona l popula t ion ; the ini t ial freedom of the trial popula t ion from tuberculosis and from contact with pu lmona ry tuberculosis at home; the protection o f a small propor t ion of those tubercul in-posi t ive at ages I5 - I 9 years in the whole count ry by previous vaccinat ion as contacts; the early discovery of some cases in the trial by the rout ine radiographic examinat ions ; and the slight difference in the age range covered by the rates (approximately 14�89 to I9�89 years for the trial popula t ion and 15 to 2o years for the na t ional populat ion) . The relative effects o f

*There is no information on the extent of this deficiency among those aged I5-19 years, but it is to be hoped that it is not as great at these ages as the figure of 27 per cent found by Logan (I959) for the proportion of deaths (at all ages) assigned to tuberculosis, which had not previously been notified. The great majority of these deaths are of persons aged 35 )-ears or more (Ministry of Health, personal communication).

T I I E SCOPE FOR BCG VACCINATION 419

t h e s e d i f f e r ences o n t h e c o m p a r i s o n c a n n o t b e assessed p rec i se ly , b u t t h e m o d e r a t e excess o f t h e i n c i d e n c e in t h e t r i a l p o p u l a t i o n , u s i n g i n t e n s i v e m e a n s o f d i s cove ry , o v e r t h e n o t i f i c a t i o n r a t e in t h e w h o l e c o u n t r y , p r o v i d e s s o m e e v i d e n c e t h a t t h e t r i a l p o p u l a t i o n was n o t gross ly u n r e p r e s e n t a t i v e in its e x p e r i e n c e o f t u b e r c u l o s i s ( M e d i c a l R e s e a r c h C o u n c i l , 1959) .

H e r e t h e e x a c t r e a s o n s for t h e d i f f e r e n c e a r e u n i m p o r t a n t . T h e v a l u e o f t h e c o m p a r i s o n is t h a t i t p e r m i t s t h e e s t i m a t e d i n c i d e n c e o f t u b e r c u l o s i s ( a m o n g those t u b e r c u l i n - p o s i t i v e a t t h e a g e o f 14 yea r s ) , v a l i d for a p o p u l a t i o n s i m i l a r to t h a t o f t h e M . R . C . t r ia l , to b e c o n v e r t e d i n t o a n e s t i m a t e o f t h e c o r r e s p o n d i n g n o t i f i c a t i o n r a t e for E n g l a n d a n d Wales . T h e e s t i m a t e d i n c i d e n c e o f o . 4 2 6 p e r i , o o o p o p u l a t i o n a g e d i 5 - i 9 yea r s in 1958 is t h u s r e d u c e d to a n o t i f i c a t i o n r a t e o f o - 4 2 6 x 1 - 6 6 i + I ' 9 4 o = o . 3 6 5 p e r I , ooo p o p u l a t i o n a g e d i 5 - i 9 yea r s i n E n g l a n d a n d Wales . T h i s r e p r e s e n t s t h a t p a r t o f t h e t o t a l n o t i f i c a t i o n r a t e a t t r i b u t a b l e to t hose a l r e a d y t u b e r c u l i n - p o s i t i v e a t t h e age o f 14 years . The Validity of the Generalization fronz a Population Similar to that of the ~ILR.C. Trial to that of England and Wales

This conversion of an incidence for a population similar to that of the M.R.C. trial to a notification rate for England and Wales is valid only if the proportion of the national notifications, attributable to those tuberculin-positive at the age of 14 years, is tbe same as the corresponding proportion for the cases in a population similar to that of the M.R.C. trial. The proportions will be the same if tuberculin sensitivity at the age of x 4 years and the subsequent risks of contracting tuberculosis are the same for the national population and for the trial population, but will not necessarily be the same otherwise. The similarity of the two proportions is therefore a major assumption in the argument.

The evidence on the similarity of the tuberculosis experience of young adults in the national anti trial populations was discussed above. There is also evidence on the similarity of the national anti trial populations in their levels of, and recent trends in, tuberculin sensitivity. In the National Tuberculin Survey in i949-5o (Medical Research Council, 1952 ) the percentage positive (to a final test with too TU) at the age of x 4 years was 43"9 per cent, tlfis representing an unweighted average of the figures for ~I areas throughout England and Wales. The corresponding unweighted average for the three areas in the M.R.C. trial in 195I-5'> (derived from Medical Research Council, ,956 ) was 4o'o per cent, a similar figure. There has also been a substantial decrease in the level of positivity throughout the country, as there has been in the population similar to that of the M.R.C. trial. In x956, for example (the earliest year for which the information is available) ~2"2 per cent ofthosegiven tuberculin tests in the official scheme for BCG vaccination at the age of 13 years were found to be 'positive' (Table II) compared with x9.6 per cent in t957 and x7. 9 per cent in 1958. Unfortunately these figures cannot be directly compared with the findings of the National Tuberculin Survey, nor with the estimates (in Table I) for a population with a similar background to that of the M.R.C. trial, because the criteria of positivity are different (Ministry of Health, 1958 ) ; some local authorities use a I TU pre-vaccinafion test (wlfich is equivalent approximately to the 3 TU test used by the M.R.C.), some a xo TU test (which is stronger) and others a multiple puncture test (which is equivalent approximately to a xoo T U test (British Tuberculosis Association, x959) ). Because of this difference, however, the percentage positive in the official scheme (if the levels of positivity were similar) would be expected to lie somewhere between the percentage poslti'ge to 3 T U and the total percentage positive (to xoo or 3 TU) in a population similar to that of the M.R.C. trial. It is therefore of interest to observe that in 1957 the estimates for a population similar to that of the M.R.C. trial at the age of 14 years (Table I) were 14 per cent positive to 3 T U (6 plus 8 per cent) and 3 ~ per cent positive to xoo or 3 T U (6 plus 8 plus 16 per cent); the national figure at the age of 13 years (Table II) was eo per cent.

These considerations indicate that it is not unrealistic to conclude that there were similar levels of, and similar trends in, tuberculin positivity, and similar risks of contracting tuberculosis, in young adults in England and Wales as in a population similar to that of the M.R.C. trial. The conversion made above will therefore be accepted as valid.

Stage 3 T h e e s t i m a t e d n o t i f i c a t i o n r a t e o f 0 .365 p e r I ,ooo , a t t r i b u t a b l e to t h o s e tuberculhz-positive a t t h e age o f I4 yea r s , d e r i v e d a b o v e for E n g l a n d a n d W a l e s in I 9 5 8 , m a y b e s u b t r a c t e d f r o m t h e t o t a l ( a d j u s t e d ) n o t i f i c a t i o n r a t e for x958 , n a m e l y 0 . 9 6 6 , to g ive o . 6 o i , w h i c h r e p r e s e n t s t h a t p a r t o f t h e n o t i f i c a t i o n r a t e a t t r i b u t a b l e to t hose tuberculin-negative a t t h e age o f 14 years . T h u s o . 6 o I - - o . 9 6 6 ~ - - 6 2 p e r c e n t is t h e p e r c e n t a g e o f t h e t o t a l n o t i f i c a t i o n s w h i c h o c c u r r e d in t hose e l ig ib le for v a c c i n a t i o n a t t h e a g e o f 14 years . I t is a s s u m e d t h a t t h e leve l o f p r o t e c t i o n f r o m

42o T U B E R C L E

PERCENTAGES OF TUBERCULOSIS NOTIFICATIONS

AMONG THOSE AGED 1 5 - 1 9 YEARS

P r e v e n t a b l e by BCG v a c c i n a t i o n

O c c u r r i n g d e s p i t e BCG v a c c i n a t i o n

I n t h o s e

100 - - i

/ . , - / J

50

t u b e r c u l i n - p o s i t i v e a t 14 y e a r s

/ 1955 1954 1955 1 956 1957 1958

YEAR

FIG. o. - The percentages of tuberculosis notifications in England and Wales at ages 15-[ 9 years, preventable by BCG vaccination at the age of 14 years of all who were then tuberculin-negative.

BCG vaccination in the country as a whole would have been the same as that for the first five years of the M.R.C. trial, namely 83.3 per cent. Then 83- 3 • 62-- IOO= 52 per cent of the notifications of all forms of tuberculosis at ages i5 - I 9 years in England and Wales in 1958 could have been prevented by BCG vaccination of all those negative to ioo TU at the age of 14 years. The adjusted notification rate of 0.966 per • represents about 2,74 ~ notifications in the whole country (applying this rate to the population figure of 2,84o,ooo in Table II). Thus (52 • 2,740 ) - too = 1,4oo (to the nearest 5 o) is the estimated number of notifications at ages x 5-I 9 years in x 958 which could have been prevented by BCG vaccination at the age of 14 years.

This final calculation is shown in the last line of Table IV. The same approach has also been used to make corresponding estimates for the years ]953 to 1957, and these also are shown in Table IV.

The Est imated Scope for BCG Vaccinat ion The estimated scope for BCG vaccination at tile age of 14 years, in terms of the

percentage of notifications at ages i5 - i 9 years in 1953 which could have been pre- vented, was 6o per cent (Table IV and Fig. 2). I f t he above estimation is valid,

T I I E SCOPE FOR BCO VACCINATION 4z i

TABLE I~ r. -- ESTIMATES OF TIlE PERCENTAGE OF ALL NOTIFICATIONS OF TUBERCULOSIS AT AGES 15--19 YEARS IN ENGLAND AND ~ALES IN TIlE YEARS 1953 TO I95~ ~rlllCII COULD IIAVE BEEN PREVENTED BY I~CG ~TACCINATION AT TIlE AGE OF 14 YEARS OF ALL ~VIIO ~VERE TtlEN TUBERCULIN NEGATIVE

Year Total

Notifications of tuberculosis (aUJorms) in England and IVales

per t,ooo population aged 15-19years

Attributable to those tuberculin-

positive at the age of t 4 years (estimated

- see text)

1953 1"8o 4 0"507 1954 i'693 0"488 1955 1"495 o'464 1956 1"279" o'432 1957 1.117" o.398 1958 o'966" o'365

Attributable to those tuberculiu-

negative at the age of

14)'ears (by difference)

1-297 I t " ~ o 5

I . o 3 I

o.847 o'719 o.6ot [

Estimated percentages of all notifications at ages z5-z9 Years

Among those eligible

for vaccination

at the age of 14)'ears

7 2 7 t 69 66 a4 62

IVhich could have been prevented

by ISCC vaccination at

the age of 14years

6o 59 57 55 53

Estimated number of

notifications preventable by

BCG vaccination at the age of 14years (to

the nearest 5 ~ )

] 2,950 2,750 2,350 1,95 ~ 1,650 1,400

*The notification rate expccted in tile absence of the official scheme for BCG vaccination at the age of 13 years.

NUMBERS OF TUBERCULOSIS NOTIFICATIONS

AMONG THOSE AGED 15-19 YEARS

5,000

P r e v e n t a b l e by BUG v a c c i n a t i o n

Occurr ing d e s p i t e BCG v a c c i n a t i o n

In those t u b e r c u l i n - p o s i t i v e at 14 y e a r s

o

4~000

5,000

2,000

1,000

0 l 1955 1954 1955 1956 1957 1958

YEAR �9 FIG. 3 - - Tile numbers of tuberculosis notifications in England and Wales at ages x5-I 9 )-ears,

preventable by BCG vaccination at the age of 14 )'ears of all who were then tuberculin-negative.

422 TUBERCLE

tile scope for BCG vaccination has steadily decreased, from about 60 per cent in I953, just after the M.R.G. trial started, to about 5 ~ per cent at the present time (i959). I t therefore appears that tim effects of the decrease in the exposure to tuberculous infection in the young adult age group, referred to above, have during this period outweighed those of the decline in the prevalence of tuberculin sensi- tivity to 3 T U in those aged 14 years. Nevertheless, even in 1958 , more than half the cases among young adults could still have been prevented by BCG vaccination.

Ahernatively, viewing the situation in terms of the mlmbers of notifications which could have been prevented, the decrease in exposure to infection in the young adult age group has caused a phenomenal drop in this measure of the scope for BCG vaccination (Table IV and Fig. 3). Whereas mass vaccination at the age of x 4 years, among those who became t5 - I 9 years of age in I953, could have prevented %95o notifications, the corresponding figure for 1958 , as already stated, was only 1,4oo , or less than half the figure five years earlier. Nevertheless, in absolute terms, tiffs is still a large number.

The Effect o f the Off ic ia l S c h e m e

In the course of deriving tim above estimates, the national notification rates at ages I5 - I 9 years fi'om 1956 to I958 were adjusted to the values expected in the absence of the official scheme for BCG vaccination at the age of 13 years. The difference between the adjusted value and tim notification rate represents the estimated reduction in incidence of tuberculosis which resulted from the oflicial scheme. In 1958 , for example, the reduction was (o.966--o.88r)----o.o85 per I,OOO population aged 15-19 years, whicla represents 0.085 • e ,84o ,ooo+1 ,ooo=o4i tuberculosis notifications. Tile corresponding reductions for ~956 and x957 were respectively 5 ~ and I56 notifications at ages 15-i 9 years. The reason for the difference between these small numbers and the totals which could have been prevented in those )'ears (see Table IX, r) is that the scheme only started in I954, and developed slowly. I t could therefore make only a partial contrihution to preventing tuberculosis in the 15-19 year age group in 1956 to x958.

D i s c u s s i o n A recent report has drawn attention to the diminished scope for BCG vaccination in tile United States of America because of tile high proportion of cases developing among those already tuberculin-positive when tested with a view to vaccination (Palmer, Shaw and Comstock, I958 ). In each of two U.S. Public Health Service trials of BCG vaccinat ion, in Georgia and Alabama and in Puerto Rico, about 75 per cent of the cases of tuberculosis expected in the absence of BOG vaccination in a six to seven }'ear follow-up occurred among those already tuberculin-positive on entry to tile trial. In the first five years of follow-up in the M.R.C. trial in Britain, however, the percentage of cases occurring among those tuberculin-positive on entry, in the absence of vaccination, was only 29 per cent (Medical Research Council, 1959).

I t was this contrast which prompted tile present study. The risk of tuberculous infection is decreasing rapidly in Britain, as in the U.S.A., and it was thus possible that the scope for BCIG vaccination might have diminished drastically in Britain in tile few years since the M.R.C. trial was undertaken. On tile present findings, there has been a moderate decline in the percentage of cases which could have been prevented by BCG vaccination at the age of 14 years, from about 6o per cent for those aged 15-x 9 years in 1953 to about 5 ~ per cent for this age group in 1958. I f the present trend in exposure to tuberculous infection continues, it seems likely that this proportion will decline still further. Thus BCG vaccination of all those tuberculin-negative (whether at 13 or at 14 years) at the present time (1959) would apparently reduce the incidence at ages i 5 - i 9 years by rather less tlaan 5o per cent.

TIlE SCOPE FOR BCG VACCINATION 423

In addition to this gradual decline in the proportion of cases preventable by BCG vaccination, however, the reduced exposure to infection has led to a very considerable decline in the total numbei's of cases occurring each year in England and Wales. The net effect has been to reduce the number of cases in the I5 - i 9 year age group, preventable by BCG vaccination, from about 2,950 in I953 to 1,4oo in I958. Thus, if the present trend in exposure to tuberculous infection continues, we may in a few years reach a situation in which the mass vaccination of school children prevents only small numbers of cases of tuberculosis in adolescents in this country. Nevertheless, provided that the immunity conferred by vaccination lasts, the vaccin- i ation of school children should continue to prevent cases developing among them when they become 20 years of age or more.

The present study has also incidentally provided estimates of the numbers of cases of tuberculosis at ages I5 - I 9 years which have so f~/r been prevented in England

a n d Wales by the official scheme for BCG vaccination at the age of x 3 years. At first sight the n u m b e r s - 5 o in I956 , x56 in I957 and 241 in x 9 5 8 - m a y seem disappointingly small in relation to the potential totals quoted above. I t must be

r emembered , however, that the scheme only started in x954, so that its full effect th roughout the I5 - I 9 year age group will not be attained until x96o. Moreover, the scheme has presumably also already "prevented some eases developing at ages 13 and 14 years, and, it is hoped, will continue to prevent cases developing at ages of 2o years and over. Nevertheless, the scheme has only developed slowly and is still far from the ideal of complete vaccination of those tuberculin-negative at the age of 13 years. In i958 only 47 per cent of those aged 13 were tuberculin tested and 37 per cent

w e r e vaccinated. I f all had been tested the proportion vaccinated would have been about 79 per cent, so that the scheme is still operating at less than half its potential capacity.

In conclusion, the estimation in this paper represents an a t tempt to use currently available data to determine the present scope for BCG vaccination. The method

i could also be used to observe future changes in the scope for BCG vaccination in this country, but it is complex and depends upon a number of assumptions. A more

d i rec t approach would now be possible, however, if a central bureau were established in connexion with the official vaccination scheme. This could collect and interpret the information on trends in tuberculin positivity at the age of 13 years, and relate the notified cases of tuberculosis at later ages to the result of the tuberculin test (if made) at the age of 13 years, and to the vaccination status. Successful enquiries of this type have been in progress under the Danish Tuberculosis Index for a number of years (Groth-Petersen, Knudsen and Wilbek, 1959), In this country

a l so they could make a valuable contribution to the eradication of tuberculosis.

S u l n n l a l ~

The second report of the Medical Research Council trial of tuberculosis vaccines i n adolescents (Medical Research Council, 1959) contained an estimate of the benefit to be expected from BCG vaccination. I f all those tuberculin-negative on entry to the trial in I95O-52 , at the age of 14 years, had been vaccinated with BCG, the reduction in the incidence of tuberculosis in the ensuing five years would

:have been 59 per cent. The present study, by taking into account the recent decrease in risk of exposure

t o tuberculous infection in England and Wales, provides similar estimates of the scope for BCG vaccination, which are more up to date and also applicable to the whole country.

O f the tuberculosis notifications among those aged I5 - I 9 years in England and Wales in i958 , it is estimated that 52 per cent could have been prevented by BCG vaccination at the age of 14 years of all who were then tuberculln-negative. This estimate for x958 is compared with that for I953, which was 6o per cent.

JJ

424 T U B E R C L E

There has thus been a moderate decline in the scope for BCG vaccination during these five years. I f the trend in exposure to tuberculous infection continues, BCG vaccination of all tuberculin-negative children who are aged 14 years now (1959) would apparent ly reduce the incidence when they become i5 - i 9 years of age by rather less than half.

In terms of the numbers of cases preventable by BCG vaccination of children aged x 4 years, the scope has declined very considerably, from about 2,95o notifications among those aged I 5 - I 9 years in I953, to x,4oo in the same age group in I958. We may in a few years reach a situation in this country in which mass vaccination of older school dfildren prevents only small numbers of cases of tuberculosis in adolescents. If, however, the protection from vaccination is maintained, cases will also be prevented in those aged 2o years and over.

I t is estimated that the official scheme for BCG vaccination at the age of 13 years, which started at the end of 1953, reduced the numbers of notifications at ages IS- I 9 years in England and Wales by 5o in x956 , 156 in x957 and 24x in 1958. These small numbers are due to incomplete coverage of the I5 - I 9 year age group in these years and the slow development of the scheme.

I t is suggested that a central bureau should be established to collect and interpret the information in connexion with the official vaccination scheme. This could make a valuable contribution to the eradication Of tuberculosis from this country.

I wish. to thank Dr P. D'Arc 3' l lart , Dr T. M. Pollock and Miss B. J . Kinsley for a number of useful discussions. I also thank Dr t tar t , as Director of the Medical Research Council's Tuberculosis Research Unit, for access to unpublished data from various enquiries currently in progress in that Unit, and tile Ministry of Health for supplying statistics of tuberculosis notifications in England and Wales at ages x5-x 9 years. The Figures were prepared by 3,liss ,M. Bragg.

References British Tuberculosis Association (1959) Tubercle, Lond., 4 o, 3x7 . Groth-Petersen, E., Knudsen, J., and Wilbek, E. (x959) Bull. Wld ltlth Org., "x, 5. Logan, W. P. D. (1959) 3Ion. Bull. Minlst. ttlth Lab. Sere., x8, 72. Medical Research Council (1952) Lar~cet, i, 775. Medical Research Council (x956) Brit. reed. o7, x, 4x3 . Medical Research Council (1958) Brit. med. o7, x, 79. " Medical Research Council (x959) Brit. reed. o7, a, 379. Ministry of Health (1949) Circular 72[49 . Ministry of Health (x953) Circular ~2[53. Ministry of Health (x958) Memo. 322]B.C.G. (Revised 1958. ) Palmer, C. E., Shaw, L. W., and Comstock, G. W. (x958) Amtr. Rer. Tuberc., 77, 877.